POU2F3-positive small cell carcinoma of the bladder: A clinicopathologic analysis of 4 cases and literature review.

POU class 2 homeobox 3 (POU2F3)-positive small cell bladder carcinoma (SCBC) is an extremely rare entity, and its clinicopathologic features have not been fully described. Here, we investigated the clinicopathologic features of 4 cases of POU2F3-positive small cell bladder carcinoma (SCBC) and reviewed the literature. We collected 12 cases of SCBC from our departmental archives and detected the expression of POU2F3 by immunohistochemical (IHC) staining. Selected cases with or without POU2F3 expression were subjected to gene expression analysis between two different groups using DESeq2 software. We identified 4 POU2F3-positive SCBC patients, 2 males and 2 females, with a mean age of 77 years. Three patients had hematuria, and 1 patient had dysuria. Radiologic findings showed a bladder mass. Pathologic diagnosis showed that 3 cases were pure SCBC and 1 was mixed urothelial cancer (UC). Histopathologically, four POU2F3-positive SCBC tumors were composed of small round cells with sparse cytoplasm, the nuclei were salt-and-pepper-like or finely granular. Tumor cells showed characteristic cytoplasmic staining with punctate positive signals for cytokeratin. Syn and CD56 were diffusely positive in all the 4 patients. CgA was positive in only one patient. POU2F3-positive SCBC showed higher expression levels of POU2F3, HMGA2 and PLCG2 genes by RNA-Seq. Our data showed the specific clinicopathologic features of 4 rare POU2F3-positive SCBC cases, and the distinct molecular feature was observed between POU2F3-positive and negative SCBC in the limited number of cases.

Patient-derived tumoroid models of pulmonary large-cell neuroendocrine carcinoma: a promising tool for personalized medicine and developing novel therapeutic strategies.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine.

A Population-Based Study of Patients With Small Cell Carcinoma of the Ovary, Hypercalcemic Type, Encompassing a 30-Year Period.

CONTEXT.­: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor, characterized by hypercalcemia and early onset and associated with germline and somatic SMARCA4 variants. OBJECTIVE.­: To identify all known cases of SCCOHT in the Slovenian population from 1991 to 2021 and present genetic testing results, histopathologic findings, and clinical data for these patients. We also estimate the incidence of SCCOHT. DESIGN.­: We conducted a retrospective analysis of hospital medical records and data from the Slovenian Cancer Registry in order to identify cases of SCCOHT and obtain relevant clinical data. Histopathologic review of tumor samples with assessment of immunohistochemical staining for SMARCA4/BRG1 was undertaken to confirm the diagnosis of SCCOHT. Germline and somatic genetic analyses were performed using targeted next-generation sequencing. RESULTS.­: Between 1991 and 2021, we identified 7 cases of SCCOHT in a population of 2 million. Genetic causes were determined in all cases. Two novel germline loss-of-function variants in SMARCA4 LRG_878t1:c.1423_1429delTACCTCA p.(Tyr475Ilefs*24) and LRG_878t1:c.3216-1G>T were identified. At diagnosis, patients were ages 21 to 41 and had International Federation of Gynecology and Obstetrics, or FIGO, stage IA-III disease. Outcomes were poor, with 6 of 7 patients dying of disease-related complications within 27 months from diagnosis. One patient had stable disease for 12 months while receiving immunotherapy. CONCLUSIONS.­: We present genetic, histopathologic, and clinical characteristics for all cases of SCCOHT identified in the Slovenian population during a 30-year period. We report 2 novel germline SMARCA4 variants, possibly associated with high penetrance. We estimate the minimal incidence of SCCOHT to be 0.12 per 1 million per year.

Clinical impact of mixed pulmonary carcinoma and carcinoid: the driver from their mono-clonal origin.

The combination of neuroendocrine/non neuroendocrine lung tumors (CNNELT) mentioned in the last edition of the World Health Organization (WHO) of Thoracic Tumors refers to small cell carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC) mixed with any other non-small cell lung carcinoma (NSCLC). Typical Carcinoid (TC)/Atypical Carcinoid (AC) combined with NSCLC is not included among this category. However, case reports of TC/AC combined with NSCLC have been described. We previously reported 2 cases of lung adenocarcinoma (LUA) mixed with carcinoid sharing mutations in both components supporting the hypothesis of a clonal origin. We extended our analysis to other four cases of mixed NSCLC-carcinoid by performing targeted-DNA and RNA-based NGS analysis in both primary and their paired lymph nodes metastasis. In all cases, LUA and AC components shared at least 1 common mutation (KRAS driver mutation p.Gly12Val in cases 1 and 3, AKAP13-RET fusion in case 2, and missense KRAS driver mutation p.Gly12Ala in case 4, reinforcing the hypothesis of a clonal origin. Moreover, the same mutation was detected in the metastasis constituted only by AC (cases 2 and 4). Although it is a rare malignancy in the lung, mixed LUA and TC/AC could be included among the histotypes for which a deep molecular characterization of both components is needed to identify the presence of potential druggable genetic alterations.

Clinical Outcomes of Small Cell Carcinoma of the Genitourinary Tract and the Prognostic Significance of the Tumor Immune Microenvironment.

PURPOSE: Small cell carcinoma of the genitourinary tract (GU SCC) is a rare disease with a poor prognosis. There are only limited treatment options due to insufficient understanding of the disease. In this study, we analyzed the clinical outcomes of patients with GU SCC and their association with the tumor immune phenotype. MATERIALS AND METHODS: Patients diagnosed with GU SCC were included. Survival outcomes according to the primary location (prostate and non-prostate) and stages (limited disease [LD] and extensive disease [ED]) were analyzed. We performed multiplex immunohistochemistry (IHC) in non-prostate SCC patients and analyzed the immune cell population. RESULTS: A total of 77 patients were included in this study. Their median age was 71 years, 67 patients (87.0%) were male, and 48 patients (62.3%) had non-prostate SCC. All patients with ED (n=31, 40.3%) received etoposide plus platinum (EP) as initial treatment and median overall survival (OS) was 9.7 months (95% confidence interval [CI], 7.1 to 18.6). Patients with LD (n=46, 59.7%) received EP followed by radiotherapy or surgery, and 24-months OS rate was 63.6% (95% CI, 49.9 to 81.0). The multiplex IHC analysis of 21 patients with non-prostate SCC showed that patients with a higher density of programmed death-ligand 1-expressing CD68+CD206+ M2-like macrophages had significantly worse OS outcomes with an adjusted hazards ratio of 4.17 (95% CI, 1.25 to 14.29; adjusted p=0.02). CONCLUSION: Patients with GU SCC had a poor prognosis, even those with localized disease. The tumor immune phenotypes were significantly associated with survival. This finding provides new insights for treating GU SCC.

A comparison of the outcomes of pulmonary versus extrapulmonary extensive-stage small cell carcinoma.

BACKGROUND: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1-0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features. AIMS: We conducted a retrospective cohort study comparing the outcomes of extensive-stage (ES) SCLC and EPSCC. METHODS: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and overall response rates (ORRs). RESULTS: Three hundred and eighty-four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5-1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58-1.46, P = 0.74) and ORR were 73% versus 68%. CONCLUSIONS: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics.

Surgery versus radiotherapy for limited-stage small cell esophageal carcinoma: a multicenter, retrospective, cohort study in China (ChiSCEC).

BACKGROUND: There is no standard management for small cell esophageal carcinoma (SCEC). The purpose of this multicenter, retrospective study (ChiSCER) was to investigate the treatment, outcomes, and risk factors impacting survival endpoints in patients with limited-stage SCEC (LS-SCEC). MATERIALS AND METHODS: Consecutive patients with LS-SCEC from 14 institutions between 2000 and 2020 in China were enrolled. Survival curves were constructed using the Kaplan-Meier method and compared using a log-rank test. Univariate and multivariate Cox regression models and propensity score matching (PSM) analysis were adopted in the prognostic analysis. Results were reported as hazard ratio (HR), 95% confidence interval (CI), and P value. Statistical significance was set as P value <0.05 in a two-tailed test. RESULTS: Among 458 LS-SCEC patients, the median age was 63 [interquartile range (IQR), 57-68] years, and 318 (69%) were males. Eighty-four (18%), 167 (36%), and 207 (45%) patients received chemotherapy (CT) alone, CT plus definitive radiotherapy (CT+RT), and CT plus radical surgery (CT+S), respectively. With a median follow-up time of 58.7 (95% CI 48.9-68.6) months, the median overall survival (OS) and 3-year OS rate for all patients 24.3 (95% CI 21.6-27) months and 37.3% (95% CI 32.8-42.5%), respectively. Multivariate analysis indicated that treatment modes, Karnofsky performance status (KPS), TNM stage, and CT cycle were independent prognostic factors for OS ( P <0.05). Compared with CT alone, patients treated with CT+RT (HR 0.57, 95% CI 0.41-0.8, P =0.001) or CT+S (HR 0.59, 95% CI 0.42-0.82, P =0.002) had an improved OS, with no significant survival differences between CT+S and CT+RT groups after multivariate and PSM analyses ( P >0.05). Subgroup analysis indicated that compared with CT+RT, patients with tumor location at lower 1/3 (HR 0.59, 95% CI 0.37-0.93, P =0.03) or tumor length >5 cm (HR 0.52, 95% CI 0.3-0.9, P =0.02) could obtain significant OS benefit from CT+S. Patients with tumor location at middle 1/3 (HR 1.55, 95% CI 1.03-2.36, P =0.04) or tumor length ≤5 cm (HR 1.49, 95% CI 1.02-2.17, P =0.04) favored CT+RT. Distant metastasis accounted for 73.7% of all treatment failures after multidisciplinary treatments. CONCLUSION: Surgery and RT were equally effective local therapies for patients with LS-SCEC. The personalized decision of local therapy should be made after comprehensive considerations on tumor location, length, comorbidities, and organ preservation.

A dramatic response to checkpoint inhibitor in a woman with small cell carcinoma of the hypercalcemic type of the ovary.

OBJECTIVE: We present the rare case of a 21 year old woman with small cell carcinoma of the right ovary of the hypercalcemic type with dramatic response to checkpoint inhibitor. METHODS: Case report. RESULTS AND CONCLUSIONS: Our patient, a 22-year old woman with small cell carcinoma of the hypercalcemic type with hepatic metastases, is currently 43 months under treatment with pembrolizumab. Last MRI revealed no viable liver metastases nor other signs of recurrence. This is the longest survival of a patient with small cell carcinoma of the ovary under therapy with checkpoint inhibitors reported in the literature so far. With this report we emphasize the importance of immunohistological testing for PD-L 1. Treating clinicians should keep off-label use of immune checkpoint blockade in mind when treating this highly aggressive tumor if all other treatment options fail.

Clonal Origin and Lineage Ambiguity in Mixed Neuroendocrine Carcinoma of the Uterine Cervix.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state.

Case series of ovarian neuroendocrine carcinoma: overview of clinicopathological features.

BACKGROUND: Ovarian neuroendocrine carcinoma (O-NEC) is a relatively uncommon neoplasm, and the current knowledge regarding its diagnosis and management is limited. In this series, our objective was to provide an overview of the clinicopathological characteristics of the disease by analyzing clinical case data to establish a theoretical foundation for the diagnosis and management of O-NEC. CASE PRESENTATION: We included three patients in the present case series, all of whom were diagnosed with primary O-NEC based on pathomorphological observation and immunohistochemistry. Patient 1 was a 62-year-old patient diagnosed with small cell carcinoma (SCC) of the pulmonary type. Post-surgery, the patient was diagnosed with stage II SCC of the ovary and underwent standardized chemotherapy; however, imaging examinations conducted at the 16-month follow-up revealed the existence of lymph node metastasis. Unfortunately, she passed away 21 months after the surgery. The other two patients were diagnosed with carcinoid tumors, one at age 39 and the other at age 71. Post-surgery, patient 2 was diagnosed with a carcinoid in the left ovary, whereas patient 3 was diagnosed with a carcinoid in her right ovary based on clinical evaluation. Neither of the cases received adjuvant therapy following surgery; however, they have both survived for 9 and 10 years, respectively, as of date. CONCLUSION: Primary O-NECs are rare and of diverse histological types, each of which has its own unique biological features and prognosis. SCC is a neoplasm characterized by high malignancy and a poor prognosis, whereas carcinoid tumors are of lesser malignancy and have a more favorable prognosis.

Novel Mouse Cell Lines and In Vivo Models for Human High-Grade Neuroendocrine Lung Carcinoma, Small Cell Lung Carcinoma (SCLC), and Large Cell Neuroendocrine Carcinoma (LCNEC).

There is a clear need to expand the toolkit of adequate mouse models and cell lines available for preclinical studies of high-grade neuroendocrine lung carcinoma (small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC)). SCLC and LCNEC are two highly aggressive tumor types with dismal prognoses and few therapeutic options. Currently, there is an extreme paucity of material, particularly in the case of LCNEC. Given the lack of murine cell lines and transplant models of LCNEC, the need is imperative. In this study, we generated and examined new models of LCNEC and SCLC transplantable cell lines derived from our previously developed primary mouse LCNEC and SCLC tumors. RNA-seq analysis demonstrated that our cell lines and syngeneic tumors maintained the transcriptome program from the original transgenic primary tumor and displayed strong similarities to human SCLC or LCNEC. Importantly, the SCLC transplanted cell lines showed the ability to metastasize and mimic this characteristic of the human condition. In summary, we generated mouse cell line tools that allow further basic and translational research as well as preclinical testing of new treatment strategies for SCLC and LCNEC. These tools retain important features of their human counterparts and address the lack of LCNEC disease models.

Small Cell Neuroendocrine Carcinoma of the Parotid Gland: An Uncommon Example of Incompletely Encapsulated Tumor Including S100 Protein-Positive Clear Cells.

Small cell carcinoma is rare in salivary glands and has recently been termed small cell neuroendocrine carcinoma. We herein describe an uncommon example arising in the parotid gland. The patient was a 75 yearold Japanese male who had swelling in the right parotid area. He underwent a superficial lobectomy and, after a histological diagnosis was made, a total parotidectomy. Histologically, the tumor had a thick hyalinized capsule that was incomplete, beyond which the tumor invaded into the surrounding parotid parenchyma. The tumor consisted of typical small basophilic cells intermingled with bland clear cells, between which a gradual transition was observed both inside and outside the capsule. Small basophilic cells were immunoreactive for chromograninA as well as synaptophysin, while clear cells were positive for S100 protein. The Ki-67 labeling rate reached 30-40% at the high points of small basophilic cells, but clear cells were minimally labelled. The present case was considered a dedifferentiated carcinoma of the parotid gland, possibly with acinic cell carcinoma as a precursor. This tumor could also be considered a "mixed exocrine-endocrine carcinoma," which may explain the histogenesis of neuroendocrine carcinomas in non-endocrine organs that are not included in the diffuse (dispersed) neuroendocrine system, such as the parotid gland.

[Small cell neuroendocrine carcinoma of the endometrium]. / Melkokletochnaya neiroendokrinnaya kartsinoma endometriya.

The article describes a rare case of small cell neuroendocrine carcinoma of the endometrium in a 67-year-old woman. According to the literature, only about 90 such observations have been described worldwide. Histological examination revealed three necessary features: the small-cell nature of the tumor, the presence of epithelial and neuroendocrine markers. An IHC study revealed a positive expression of Syn, Chrom A, CD56, CK AE1/AE3 markers; the proliferative activity index was 70%.